tbuckley/cabot-search huggingface dataset:
Impact of Hepatitis C Treatment Uptake on Cirrhosis and Mortality in Persons Who Inject Drugs
Authors: Javier A. Cepeda, David L. Thomas, Jacqueline Astemborski, Jacqueline E. Rudolph, Rachel Gicquelais, Gregory D. Kirk, Shruti H. Mehta
Journal: Annals of Internal Medicine (2022)

Hepatitis C virus (HCV) infection can be cured, and the United States has joined the World Health Organization in calling for HCV elimination by 2030. However, historically low uptake of HCV treatment among people who inject drugs (PWID) threatens HCV elimination and exacerbates social and racial health disparities. To assess whether all-oral HCV treatments were accessed by PWID and reduced liver disease burden and mortality. Community-based, longitudinal cohort study of persons with a history of injection drug use. Baltimore, Maryland. 1323 participants enrolled in the ALIVE (AIDS Linked to the IntraVenous Experience) study from 2006 to 2019 and chronically infected with HCV. Liver stiffness measures (LSMs) by transient elastography, HCV RNA, and mortality from the National Death Index. Among 1323 persons with evidence of chronic HCV infection at baseline, the median age was 49 years. Most were Black (82%), male (71%), and HIV-negative (66%). The proportion in whom HCV RNA was detected decreased from 100% (by definition) in 2006 to 48% in 2019. Across 10 350 valid LSMs, cirrhosis was detected in 15% of participants in 2006, 19% in 2015, and 8% in 2019. Undetectable HCV RNA was significantly associated with reduced odds of cirrhosis (adjusted odds ratio, 0.28 [95% CI, 0.17 to 0.45]) and reduced all-cause mortality risk (adjusted hazard ratio, 0.54 [CI, 0.38 to 0.77]). Noninvasive markers of liver fibrosis have not been validated in persons with sustained virologic response. Many community-based PWID in Baltimore are receiving HCV treatment, which is associated with sharp decreases in liver disease and mortality. Additional efforts will be needed to reduce residual barriers to treatment and to eliminate HCV as a public health threat for PWID. National Institutes of Health.
Fever therapy in febrile adults: systematic review with meta-analyses and trial sequential analyses
Authors: Johan Holgersson, Ameldina Ceric, Naqash Sethi, Niklas Nielsen, Janus Christian Jakobsen
Journal: BMJ (2022)

Abstract Objective To investigate the effects of fever therapy compared with no fever therapy in a wide population of febrile adults. Design Systematic review with meta-analyses and trial sequential analyses of randomised clinical trials. Data sources CENTRAL, BIOSIS, CINAHL, MEDLINE, Embase, LILACS, Scopus, and Web of Science Core Collection, searched from their inception to 2 July 2021. Eligibility criteria Randomised clinical trials in adults diagnosed as having fever of any origin. Included experimental interventions were any fever therapy, and the control intervention had to be no fever therapy (with or without placebo/sham). Data extraction and synthesis Two authors independently selected studies, extracted data, and assessed the risk of bias. Primary outcomes were all cause mortality and serious adverse events. Secondary outcomes were quality of life and non-serious adverse events. Aggregate data were synthesised with meta-analyses, subgroup analyses, and trial sequential analyses, and the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Results Forty two trials assessing 5140 participants were included. Twenty three trials assessed 11 different antipyretic drugs, 11 trials assessed physical cooling, and eight trials assessed a combination of antipyretic drugs and physical cooling. Of the participants, 3007 were critically ill, 1892 were non-critically ill, 3277 had infectious fever, and 1139 had non-infectious fever. All trials were assessed as being at high risk of bias. Meta-analysis and trial sequential analysis showed that the hypothesis that fever therapy reduces the risk of death (risk ratio 1.04, 95% confidence interval 0.90 to 1.19; I 2 =0%; P=0.62; 16 trials; high certainty evidence) and the risk of serious adverse events (risk ratio 1.02, 0.89 to 1.17; I 2 =0%; P=0.78; 16 trials; high certainty evidence) could be rejected. One trial assessing quality of life was included, showing no difference between fever therapy and control. Meta-analysis and trial sequential analysis showed that the hypothesis that fever therapy reduces the risk of non-serious adverse events could be neither confirmed nor rejected (risk ratio 0.92, 0.67 to 1.25; I 2 =66.5%; P=0.58; four trials; very low certainty evidence). Conclusions Fever therapy does not seem to affect the risk of death and serious adverse events. Systematic review registration PROSPERO CRD42019134006
Reply
Authors: Lukas Hartl, Thomas Reiberger, Michael Trauner
Journal: Hepatology (2022)

We thank Jiang et al.[1] for the interest in our study on progressive cholestasis and secondary sclerosing cholangitis (SSC) after coronavirus disease 2019 (COVID‐19) in patients with chronic liver disease (CLD)[2] that has raised clinical awareness for long‐term hepatobiliary complications of COVID‐19. Importantly, patients with CLD, especially NAFLD/NASH, and those with severe courses of COVID‐19 requiring admission to the intensive care unit (ICU) were at particularly high risk for developing progressive cholestasis and irreversible bile duct damage. Jiang et al. argue that the population characteristics of the two groups could have been different. However, we want to emphasize that important clinical parameters[3] including age, sex, severity of preexisting CLD, extracorporeal membrane oxygenation, and follow‐up duration did not differ between our control cohort and patients with CLD and COVID‐19. Indeed, patients in the control cohort all were ICU patients, they were intubated and died more frequently than the patients with CLD and COVID‐19. This indicates a similarly—or even more—severe state of critical illness of patients in our control cohort versus the patients with CLD and COVID‐19. Thus, the increased prevalence of SSC among the CLD‐COVID cohort may be even more significant, because hypoxemia, mechanical ventilation, and systemic inflammatory response syndrome are all risk factors for SSC development.[4,5] Concerning the risk factors for SSC mentioned by Jiang et al., we are happy to provide further details. Apart from one patient with a history of cholecystectomy, none of the patients with CLD and COVID‐19 developing SSC had previous cholelithiasis, drug‐resistant bacterial infection, biliary tract surgery, or immune dysfunction. Moreover, Jiang et al. raised the relevant point of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) variants. In our study, 50% (n = 5/10) of patients with CLD developing SSC were infected with the initial variation of SARS‐CoV‐2, whereas the Alpha variant (B.1.1.7) was detected in 40% (n = 4/10), and one patient was infected with the Delta variant (B.1.617.2). Because SARS‐CoV‐2 superantigen mechanisms in a previously sensitized host may be involved in biliary damage and/or SSC development, future studies should investigate whether distinct variants of SARS‐CoV‐2 (carrying different viral epitopes) are particularly associated with cholestasis and bile duct damage. CONFLICT OF INTEREST Michael Trauner consults for, is on the speakers' bureau for, and received grants from Falk, Gilead, and Intercept. He consults for and received grants from AbbVie and Alberio. He is on the speakers' bureau for and received grants from Merck Sharp & Dohme and Roche. He consults for BiomX, Boehringer Ingelheim, Genfit, Hightide, Shire, Novartis, Pliant, Regulus, and Siemens. He received grants from Alryluem, Cymabay, Janssen, Takeda, and Ultragenyx. He is the coinventor of patents on the medical use of 24‐norursodeoxycholic acid.
Letter to the editor: Complications following SARS‐CoV‐2 infection in patients with chronic liver disease
Authors: Shi‐Tao Jiang, Lei Zhang, Yi‐Yao Xu, Xin Lu
Journal: Hepatology (2022)

To the editor, Recently, Hartl et al. reported a study on liver‐related complications after severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection.[1] This single‐center retrospective study includes 65 patients with NAFLD/NASH‐predominant chronic liver disease (CLD). They described the pattern of progression of cholestatic liver injury following SARS‐CoV‐2 infection. Hartl et al. noted that the patients were more likely to develop secondary sclerosing cholangitis (SSC) than control patients infected with non‐COVID‐19 pneumonia. This study provided essential data for our understanding of clinical outcomes following SARS‐CoV‐2 infection in patients with CLD. In addition to the results already shown in the study, we believe that some issues deserve further discussion. First, this study selected patients hospitalized for COVID‐19 at the Vienna General Hospital from March 2020 to July 2021. The significant variants have changed many times, such as alpha, beta, gamma, delta, and omicron. Different variants could exhibit different replicative capacities and pathogenicity.[2] We hope the authors provide the main types of variants infected by the enrolled patients, which would help avoid overinterpretation of the study results. Second, this study used a case–control study design to assess the potential impact of SARS‐CoV‐2 infection on patients with CLD. However, the authors did not provide the screening process and matching method of patients in the control group. In addition, the patients in the control group were all from the intensive care unit ward, and their intubation rate and mortality were significantly higher than those in the COVID‐19 group. If the population characteristics of the control group and the study group were different, the case–control design of the study was not reasonable. Furthermore, the analysis did not include important factors that could lead to SSC, such as whether the patients had a history of biliary tract surgery, cholelithiasis, drug‐resistant bacterial infection, and immune dysfunction.[3] We believe that the authors should try to perform a logistic regression analysis with the occurrence of SSC as the outcome in order to further quantify the impact of SARS‐CoV‐2 infection on patients with CLD. Finally, we suggest that the authors use a directed acyclic graph to select covariates to exclude mediators' influence on the regression model.[4] For example, the authors included both bilirubin and the model of end‐stage liver disease (MELD) score in a univariate Cox regression analysis. However, the MELD score already included the assessment of bilirubin, which may affect the accuracy of the regression model to some extent. FUNDING INFORMATION Supported by CAMS Innovation Fund for Medical Sciences (CIFMS) (No. 2020‐I2M‐CT‐B‐026). CONFLICT OF INTEREST Nothing to report.
Bipolar Disorder
Authors: Mark S. Bauer
Journal: Annals of Internal Medicine (2022)

Bipolar disorder (BD) affects approximately 2% of U.S. adults and is the most costly mental health condition for commercial insurers nationwide. Rates of BD are elevated among persons with depression, anxiety disorders, and substance use disorders—conditions frequently seen by primary care clinicians. In addition, antidepressants can precipitate manic or hypomanic symptoms or rapid cycling in persons with undiagnosed BD. Thus, screening in these high-risk groups is indicated. Effective treatments exist, and many can be safely and effectively administered by primary care clinicians.
DC ENaC-Dependent Inflammasome Activation Contributes to Salt-Sensitive Hypertension
Authors: Ashley Pitzer, Fernando Elijovich, Cheryl L. Laffer, Lale A. Ertuglu, Melis Sahinoz, Mohammad Saleem, Jaya Krishnan, Thanvi Dola, Luul A. Aden, Quanhu Sheng, Michael A. Raddatz, Celestine Wanjalla, Suman Pakala, Sean S. Davies, David M. Patrick, Valentina Kon, T. Alp Ikizler, Thomas Kleyman, Annet Kirabo
Journal: Circulation Research (2022)

Salt sensitivity of blood pressure is an independent predictor of cardiovascular morbidity and mortality. The exact mechanism by which salt intake increases blood pressure and cardiovascular risk is unknown. We previously found that sodium entry into antigen-presenting cells (APCs) via the amiloride-sensitive epithelial sodium channel EnaC (epithelial sodium channel) leads to the formation of IsoLGs (isolevuglandins) and release of proinflammatory cytokines to activate T cells and modulate salt-sensitive hypertension. In the current study, we hypothesized that ENaC-dependent entry of sodium into APCs activates the NLRP3 (NOD [nucleotide-binding and oligomerization domain]-like receptor family pyrin domain containing 3) inflammasome via IsoLG formation leading to salt-sensitive hypertension.
SMYD3 Impedes Small Cell Lung Cancer Sensitivity to Alkylation Damage through RNF113A Methylation–Phosphorylation Cross-talk
Authors: Valentina Lukinović, Simone Hausmann, Gael S. Roth, Clement Oyeniran, Tanveer Ahmad, Ning Tsao, Joshua R. Brickner, Alexandre G. Casanova, Florent Chuffart, Ana Morales Benitez, Jessica Vayr, Rebecca Rodell, Marianne Tardif, Pascal W.T.C. Jansen, Yohann Couté, Michiel Vermeulen, Pierre Hainaut, Pawel K. Mazur, Nima Mosammaparast, Nicolas Reynoird
Journal: Cancer Discovery (2022)

Abstract Small cell lung cancer (SCLC) is the most fatal form of lung cancer, with dismal survival, limited therapeutic options, and rapid development of chemoresistance. We identified the lysine methyltransferase SMYD3 as a major regulator of SCLC sensitivity to alkylation-based chemotherapy. RNF113A methylation by SMYD3 impairs its interaction with the phosphatase PP4, controlling its phosphorylation levels. This cross-talk between posttranslational modifications acts as a key switch in promoting and maintaining RNF113A E3 ligase activity, essential for its role in alkylation damage response. In turn, SMYD3 inhibition restores SCLC vulnerability to alkylating chemotherapy. Our study sheds light on a novel role of SMYD3 in cancer, uncovering this enzyme as a mediator of alkylation damage sensitivity and providing a rationale for small-molecule SMYD3 inhibition to improve responses to established chemotherapy. Significance: SCLC rapidly becomes resistant to conventional chemotherapy, leaving patients with no alternative treatment options. Our data demonstrate that SMYD3 upregulation and RNF113A methylation in SCLC are key mechanisms that control the alkylation damage response. Notably, SMYD3 inhibition sensitizes cells to alkylating agents and promotes sustained SCLC response to chemotherapy. This article is highlighted in the In This Issue feature, p. 2007
Elucidating the Clinical Implications and Pathophysiology of Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction: A Call to Action: A Science Advisory From the American Heart Association
Authors: Evan L. Brittain, Thenappan Thenappan, Jessica H. Huston, Vineet Agrawal, Yen-Chun Lai, Debra Dixon, John J. Ryan, Eldrin F. Lewis, Margaret M. Redfield, Sanjiv J. Shah, Bradley A. Maron
Journal: Circulation (2022)

This science advisory focuses on the need to better understand the epidemiology, pathophysiology, and treatment of pulmonary hypertension in patients with heart failure with preserved ejection fraction. This clinical phenotype is important because it is common, is strongly associated with adverse outcomes, and lacks evidence-based therapies. Our goal is to clarify key knowledge gaps in pulmonary hypertension attributable to heart failure with preserved ejection fraction and to suggest specific, actionable scientific directions for addressing such gaps. Areas in need of additional investigation include refined disease definitions and interpretation of hemodynamics, as well as greater insights into noncardiac contributors to pulmonary hypertension risk, optimized animal models, and further molecular studies in patients with combined precapillary and postcapillary pulmonary hypertension. We highlight translational approaches that may provide important biological insight into pathophysiology and reveal new therapeutic targets. Last, we discuss the current and future landscape of potential therapies for patients with heart failure with preserved ejection fraction and pulmonary vascular dysfunction, including considerations of precision medicine, novel trial design, and device-based therapies, among other considerations. This science advisory provides a synthesis of important knowledge gaps, culminating in a collection of specific research priorities that we argue warrant investment from the scientific community.
Medical domain knowledge in domain-agnostic generative AI
Authors: Jakob Nikolas Kather, Narmin Ghaffari Laleh, Sebastian Foersch, Daniel Truhn
Journal: npj Digital Medicine (2022)

The text-guided diffusion model GLIDE (Guided Language to Image Diffusion for Generation and Editing) is the state of the art in text-to-image generative artificial intelligence (AI). GLIDE has rich representations, but medical applications of this model have not been systematically explored. If GLIDE had useful medical knowledge, it could be used for medical image analysis tasks, a domain in which AI systems are still highly engineered towards a single use-case. Here we show that the publicly available GLIDE model has reasonably strong representations of key topics in cancer research and oncology, in particular the general style of histopathology images and multiple facets of diseases, pathological processes and laboratory assays. However, GLIDE seems to lack useful representations of the style and content of radiology data. Our findings demonstrate that domain-agnostic generative AI models can learn relevant medical concepts without explicit training. Thus, GLIDE and similar models might be useful for medical image processing tasks in the future - particularly with additional domain-specific fine-tuning.
Predicting Firearm Suicide—Small Steps Forward With Big Data
Authors: Marian E. Betz, Jennifer M. Boggs, Foster R. Goss
Journal: JAMA Network Open (2022)

Hannah S. Laqueur, PhD, MA, MPA; Colette Smirniotis, PhD, MS; Christopher McCort, MS; Garen J. Wintemute, MD, MPH
Virtual reality in intensive care
Authors: Raphael R. Bruno, Nico Bruining, Christian Jung, Malte Kelm, Georg Wolff, Bernhard Wernly
Journal: Intensive Care Medicine (2022)

A tool for the intensive care unit emerging from the entertainment industryVirtual and augmented reality (VR/AR) are becoming increasingly familiar to us from science fiction and are now commonly used for entertainment.In VR, the user wears special glasses to immerse them entirely into an artificial three-dimensional world (VR) or to integrate different imaging modalities superimposing virtual elements into a real-world environment (AR).For VR, various applications are helpful in intensive care medicine for healthcare providers, patients, and their relatives: education, training and relaxation [1].Accumulating evidence suggests that VR will find its role in the intensive care unit (ICU), although large studies are currently lacking [2,3].Figure 1 illustrates some potential roles for VR in the ICU: to train ICU staff to perform practical procedures or to setup up devices (A) or to distract and comfort patients during procedures (B).In addition, VR could help to alleviate delirium and anxiety (C), and improve mobilisation and weaning.At present, it is challenging to delineate the "real" evidence for VR use in intensive care medicine.This brief overview presents the available and emerging options and the latest evidence.
Pathogenic neuropsychiatric effect of stress-induced microglial interleukin 12/23 axis in systemic lupus erythematosus
Authors: Nobuya Abe, Masato Tarumi, Yuichiro Fujieda, Nobuhiko Takahashi, Kohei Karino, Mona Uchida, Michihito Kono, Yuki Tanaka, Rie Hasebe, Masaru Kato, Olga Amengual, Yoshiyuki Arinuma, Kenji Oku, Wakiro Sato, Khin Khin Tha, Miwako Yamasaki, Masahiko Watanabe, Tatsuya Atsumi, Masaaki Murakami
Journal: Annals of the Rheumatic Diseases (2022)

Objectives The central nervous system disorder in systemic lupus erythematosus (SLE), called neuropsychiatric lupus (NPSLE), is one of the most severe phenotypes with various clinical symptoms, including mood disorder, psychosis and delirium as diffuse neuropsychological manifestations (dNPSLE). Although stress is one of the aggravating factors for neuropsychiatric symptoms, its role in the pathogenesis of dNPSLE remains to be elucidated. We aimed to investigate stress effects on the neuropsychiatric pathophysiology in SLE using lupus-prone mice and patients’ data. Methods Sleep disturbance stress (SDS) for 2 weeks was placed on 6–8-week-old female MRL/ lpr and control mice. Behavioural phenotyping, histopathological analyses and gene and protein expression analyses were performed to assess SDS-induced neuroimmunological alterations. We also evaluated cytokines of the cerebrospinal fluid and brain regional volumes in patients with dNPSLE and patients with non-dNPSLE. Results SDS-subjected MRL/ lpr mice exhibited less anxiety-like behaviour, whereas stressed control mice showed increased anxiety. Furthermore, stress strongly activated the medial prefrontal cortex (mPFC) in SDS-subjected MRL/ lpr . A transcriptome analysis of the PFC revealed the upregulation of microglial activation-related genes, including Il12b . We confirmed that stress-induced microglial activation and the upregulation of interleukin (IL) 12/23p40 proteins and increased dendritic spines in the mPFC of stressed MRL/ lpr mice. IL-12/23p40 neutralisation and tyrosine kinase 2 inhibition mitigated the stress-induced neuropsychiatric phenotypes of MRL/ lpr mice. We also found a higher level of cerebrospinal fluid IL-12/23p40 and more atrophy in the mPFC of patients with dNPSLE than those with non-dNPSLE. Conclusions The microglial IL-12/23 axis in the mPFC might be associated with the pathogenesis and a promising therapeutic target for dNPSLE.
Developmental changes in iron metabolism and erythropoiesis in mice with human gain‐of‐function erythropoietin receptor
Authors: Barbora Kralova, Lucie Sochorcova, Jihyun Song, Ondrej Jahoda, Katarina Hlusickova Kapralova, Josef T. Prchal, Vladimir Divoky, Monika Horvathova
Journal: American Journal of Hematology (2022)

Abstract Iron availability for erythropoiesis is controlled by the iron‐regulatory hormone hepcidin. Increased erythropoiesis negatively regulates hepcidin synthesis by erythroferrone (ERFE), a hormone produced by erythroid precursors in response to erythropoietin (EPO). The mechanisms coordinating erythropoietic activity with iron homeostasis in erythrocytosis with low EPO are not well defined as exemplified by dominantly inherited (heterozygous) gain‐of‐function mutation of human EPO receptor ( mtHEPOR ) with low EPO characterized by postnatal erythrocytosis. We previously created a mouse model of this mtHEPOR that develops fetal erythrocytosis with a transient perinatal amelioration of erythrocytosis and its reappearance at 3–6 weeks of age. Prenatally and perinatally, mtHEPOR heterozygous and homozygous mice (differing in erythrocytosis severity) had increased Erfe transcripts, reduced hepcidin, and iron deficiency. Epo was transiently normal in the prenatal life; then decreased at postnatal day 7, and remained reduced in adulthood. Postnatally, hepcidin increased in mtHEPOR heterozygotes and homozygotes, accompanied by low Erfe induction and iron accumulation. With aging, the old, especially mtHEPOR homozygotes had a decline of erythropoiesis, myeloid expansion, and local bone marrow inflammatory stress. In addition, mtHEPOR erythrocytes had a reduced lifespan. This, together with reduced iron demand for erythropoiesis, due to its age‐related attenuation, likely contributes to increased iron deposition in the aged mtHEPOR mice. In conclusion, the erythroid drive‐mediated inhibition of hepcidin production in mtHEPOR mice in the prenatal/perinatal period is postnatally abrogated by increasing iron stores promoting hepcidin synthesis. The differences observed in studied characteristics between mtHEPOR heterozygotes and homozygotes suggest dose‐dependent alterations of downstream EPOR stimulation.